By Joy Moverley, DHSc, MPH, PA-C; Bhavya Chhabra, OMS-IV; Kasra Soltani Nia, OMS-IV; Kirsten Alliston, MPH(c), PA-S3; and Clipper F. Young, PharmD, MPH, BC-ADM, CDCES, BCGP, APh, FADCES
Obesity is a global health crisis, since it is one of the leading causes of morbidity and economic burden because it contributes to the risk of developing chronic diseases, including type 2 diabetes, heart disease, depression, cancers, and metabolic syndrome. In recent years, pharmacotherapies have continued to gain popularity as people struggle to achieve weight loss with lifestyle interventions alone. Modern pharmacotherapies address the multifaceted pathophysiology causes of obesity, thus mitigating its potential health effects.
Understanding the clinical indications of each medication used in this space is essential for healthcare providers to recommend the most suitable option(s) for those who struggle with obesity. This review article synthesizes and highlights the major U.S. Food and Drug Administration (FDA)-approved pharmacotherapeutic agents available for weight reduction. It also discusses some special considerations between obesity and selected chronic conditions. Special focus is placed on incretin-based therapies, which have revolutionized obesity treatment, achieving weight loss comparable to bariatric surgery and improving cardiometabolic outcomes. Although the medications reviewed have provided opportunities for achieving weight loss and potentially mitigating the associated health risks, careful consideration of person-specific characteristics and the agents’ potential side effects, in conjunction with lifestyle modifications, is critical to optimize treatment outcomes.
Introduction
Obesity is a complex, chronic condition that has become a major public health concern worldwide, contributing to numerous health complications and significant economic burdens. Affecting nearly one out of every seven people, obesity is projected to have a substantial global economic effect, with estimates approaching $4 trillion by 2035.1 In the United States alone, the rising cases of obesity have become a complex public health crisis. One out of five children is obese, and two out of five adults are obese.2
A recent study capturing data from 161,795 U.S. adults between 2013 and 2017 revealed that those with a higher social determinants of health (SDOH) burden were associated with higher odds of obesity.3 Non-Hispanic Black adults and Hispanic adults had the highest prevalence of obesity at 49.9% and 45.6%, respectively.4
Age also must be considered when assessing the severity of obesity. In the United States, 19.7% of children are classified as obese.4 Childhood obesity follows similar racial and ethnic patterns as adults, disproportionately affecting non-Hispanic Black (24.8%) and Hispanic (26.2%) children compared to non-Hispanic white children (16.6%) and non-Hispanic Asian children (9%). Obesity prevalence remains highest in lower- and middle-income groups.
Obesity can further lead to higher risks for many health effects, e.g., all-cause mortality, hypertension, dyslipidemia, cardiovascular diseases, type 2 diabetes mellitus (T2DM), obstructive sleep apnea, osteoarthritis, some cancers, and more.5 Given this causality, obesity reduction also is effective at subsequent health risk mitigation. Multiple studies demonstrate that weight reduction can delay or prevent prediabetes progressing toward T2DM and is beneficial in the management of many associated chronic conditions.6 However, the Look AHEAD Trial, published in 2013, that studied overweight and obese participants living with T2DM, concluded that an intensive lifestyle modification program for weight loss did not lead to a reduction of cardiovascular events in this population.7
Lifestyle modifications, medical nutrition therapy, pharmacological interventions, and surgical procedures continue to be the mainstay options for weight management. This review describes the pharmacological agents available for weight reduction and discusses some special considerations regarding obesity and selected chronic conditions.
Pharmacotherapeutic Options for Obesity
There currently are 11 FDA-approved medications for the treatment and management of obesity in adults, four of which are approved for short-term use (up to 12 weeks) and seven for long-term use.8 The FDA recommends considering obesity pharmacotherapy when a person’s body mass index (BMI) is greater than 30 kg/m2 or greater than 27 kg/m2 with an obesity-related comorbid condition if the person has not met weight loss goals with lifestyle intervention alone.8 The threshold for individuals of Asian background is a BMI of greater than 27.5 kg/m2 or greater than 23 kg/m2 with comorbid conditions.8
This section uses a case-based approach to explore the different classes of pharmacotherapeutic agents used in obesity treatment. Tables 1-3 provide an overview of all medications discussed. Weight management drugs are not recommended for certain subgroups, including children younger than 8 years of age, patients who previously experienced an adverse reaction from an agent within the weight management drug classes, and pregnant and lactating individuals.
Table 1. Medication Dosing, Contraindications/Warnings, and Side Effects | |||
Medications (Generic Name) | Dosing | Contraindications and Warnings | Common Side Effects |
Liraglutide11 | Initial: 0.6 mg subcutaneously daily Doses can be increased weekly until the maximum dose of 3 mg daily. Consider postponing the next dose by an additional week if the patient cannot tolerate the current dose. | CI: Pregnancy, pancreatitis, medullary thyroid cancer, and multiple endocrine neoplasia 2A or 2B Warnings: For patients using liraglutide and semaglutide alongside insulin or sulfonylureas, monitor blood glucose regularly due to the risk of hypoglycemia. | GI side effects such as nausea, vomiting, and diarrhea |
Semaglutide (injectable)12 | Initial: 0.25 mg subcutaneously weekly Doses can be increased every four weeks until the maximum dose of 2.4 mg weekly. Consider postponing the next dose by an additional four weeks if the patient cannot tolerate the current dose. | ||
Tirzepatide81 | Initial: 2.5 mg subcutaneously weekly Doses can be increased every four weeks until the maximum dose of 15 mg weekly. | CI: Pregnancy, pancreatitis, medullary thyroid cancer, severe gastrointestinal disease, acute kidney injury, acute gallbladder disease, diabetic retinopathy complications Warnings: For patients using tirzepatide alongside insulin or sulfonylureas, monitor blood glucose regularly due to risk of hypoglycemia. | GI side effects, including nausea, vomiting, and diarrhea |
Phentermine- topiramate60 | Initial: 3.75 mg phentermine/23 mg topiramate daily every morning for 14 days Then, the dose can be increased to 7.5 mg phentermine/46 mg topiramate daily for 12 weeks. After 12 weeks of previous dose, this medication can be titrated based on individual’s response to the maximum dose of 15 mg phentermine/92 mg topiramate once daily. | CI: Pregnancy, hyperthyroidism, or glaucoma Warnings: Discontinue usage within 14 days after taking MAO inhibitors. Use with caution in patients with a history of renal stones. | Anticholinergic effects: dry mouth, constipation, cognitive disturbances, paresthesia, mood changes Other effects: increase in heart rate and blood pressure. |
CI: contraindication; GI: gastrointestinal; MAO: monoamine oxidase | |||
Table 1. Medication Dosing, Contraindications/Warnings, and Side Effects, continued | |||
Medications (Generic Name) | Dosing | Contraindications and Warnings | Common Side Effects |
Naltrexone- bupropion65 | Initial dose: 1 tablet (8 mg naltrexone/90 mg bupropion) daily for one week Titration can increase one tablet weekly until reaching the maximum daily dose. The maximum daily dose is four tablets (32 mg naltrexone/360 mg bupropion) daily (two tablets in the morning and two tablets in the evening). | CI: Pregnancy, hyperthyroidism, or glaucoma Warnings: Discontinue usage within 14 days after taking MAO inhibitors. Use with caution in patients with a history of renal stones | Constipation, dry mouth, dizziness, nausea, vomiting, headaches, increase in blood pressure and heart rate |
Orlistat46 | Non-prescription dose: 60 mg three times a day with fat-containing meals Prescription dose: 120 mg three times a day with fat-containing meals | CI: Pregnancy, chronic malabsorption, cholestasis, history of calcium oxalate stones, or known hypersensitivity Warning: use caution in nursing people, not known if orlistat is present in human milk. Warning: severe liver injury and acute hepatic failure have been reported. | Gastrointestinal effects: diarrhea, flatulence, bloating, abdominal pain, dyspepsia, oily/fatty stool, increased defecation, and fecal incontinence |
Phentermine49 | Immediate release (IR): 15 mg to 37.5 mg daily or divided twice daily Orally disintegrating tablet: IR (Lomaira): 8 mg three times daily before meals | CI: Cardiovascular disease (e.g., uncontrolled hypertension, coronary artery disease, heart failure, history of stroke), hyperthyroidism, glaucoma, an agitated state (severe anxiety or agitation), or a history of substance use disorder. Discontinue use in patients who are taking MAO inhibitors, or within 14 days of stopping, pregnancy, or nursing. Warning: Rare cases of primary pulmonary hypertension have been reported. | Increased heart rate and blood pressure, insomnia, dry mouth, constipation, and nervousness |
Phendimetrazine51 | IR: 17.5 mg to 35 mg two or three times daily at one hour before meals Maximum dose: 70 mg three times daily Sustained release (SR): 105 mg daily in the morning | ||
CI: contraindication; GI: gastrointestinal; MAO: monoamine oxidase | |||
Table 2. Medication Considerations | |||
Medication (Generic Name) | Considerations | ||
Renal Impairment | Hepatic Impairment | Pregnancy | |
Liraglutide11 | No dose adjustment is recommended; however, use the agents with caution in cases of renal or hepatic impairment. | Stop prior to a planned pregnancy. | |
Semaglutide (injectable)12 | Stop semaglutide for at least two months prior to a planned pregnancy because of the long half-life. | ||
Tirzepatide81 | Stop at least two months prior to a planned pregnancy. | ||
Phentermine- topiramate60 | CrCl < 50 mL/min: maximum dose at phentermine 7.5 mg/ topiramate 46 mg once daily | Mild hepatic impairment: no dose adjustment necessary Moderate hepatic impairment: maximum dose at phentermine 7.5 mg/topiramate 46 mg once daily Do not use in patients with severe hepatic impairment. | Stop prior to a planned pregnancy. |
Naltrexone- bupropion65 | Mild renal impairment: No dose adjustment necessary. Moderate to severe renal impairment: maximum dose of one tablet (naltrexone 8 mg/bupropion 90 mg) twice daily Patients with ESRD should avoid naltrexone-bupropion use. | Mild hepatic impairment: No dose adjustment necessary. Moderate hepatic impairment: maximum dose of one tablet (naltrexone 8 mg/bupropion Patients with severe hepatic impairment should avoid naltrexone-bupropion use. | |
Orlistat46 | Use with caution; no dose adjustment recommended. | ||
Phentermine49 | Reduced renal function of eGFR from 15 to 29 mL/min/1.73 m2: maximum daily dose of 15 mg of phentermine Reduced renal function of eGFR | No adjustment necessary. | |
Phendimetrazine51 | Use with caution: no dose adjustment recommended. | ||
CrCl: creatinine clearance; ESRD: end-stage renal disease; eGFR: estimated glomerular filtration rate | |||
Table 3. Medication Cost | |
Medication (Generic Name) | Median 30-Day Supply Cost/Average Wholesale Price (NADAC) |
Liraglutide11 | $1,619/$1,296 |
Semaglutide (injectable)12 | $1,619/$1,296 |
Tirzepatide81 | $1,272/$1,017 |
Phentermine-topiramate60 | $237/NA |
Naltrexone-bupropion65 | $750/NA |
Orlistat46 | For RX version, $843/$677 |
Phentermine49 | $43/$3 |
Phendimetrazine51 | |
NADAC: National Average Drug Acquisition Cost | |
Glucagon-Like Peptide-1 Receptor Agonists: Semaglutide and Liraglutide
Case Vignette 1, Part 1
A 42-year-old female with a BMI of 42 comes to the clinic requesting medication to help with weight loss. She has no family history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia (MEN) type 2. She is amenable to injections and wishes to try a glucagon-like peptide-1 receptor agonist (GLP1-RA) after hearing about the weight loss success of this class of medications from her friends.
The GLP-1 RAs are one of the newest medication classes for weight management. GLP-1 RAs initially were approved for treating T2DM because of their ability to improve glycemic management in T2DM by influencing mechanisms to induce weight loss. The FDA approved liraglutide as the first GLP-1 RA in 2014 for treating T2DM and obesity. In 2021, semaglutide was the second FDA-approved GLP-1 RA for obesity treatment.9,10
Background Information
GLP-1 RAs are considered first-line therapy for overweight or obese individuals with or without T2DM. Although both agents are administered subcutaneously, semaglutide is administered weekly, while liraglutide is administered daily.11,12 Some patients might prefer semaglutide because of its weekly dosing and superior efficacy in weight loss.13
Mechanism of Action
GLP-1 RAs reduce body weight by interacting with GLP-1 receptors throughout the body, increasing insulin sensitivity and influencing pathways imperative to obesity treatment.14 By accessing these areas, these agents have direct and indirect modulation of neural circuits involved in feeding behavior, reward processing, and energy balance.15 GLP-1 receptor activation increases insulin secretion via the pancreatic L cells, slows gastric emptying, and suppresses glucagon release from the pancreas, reducing blood glucose levels.16
Efficacy
The Semaglutide Treatment Effect in People with Obesity (STEP) 5 Trial evaluated the efficacy and safety of once-weekly 2.4-mg semaglutide compared to placebo. The treatment resulted in significant and sustained weight loss over 104 weeks in adults with obesity or overweight with at least one weight-related comorbidity.17 The STEP 8 Trial further explored semaglutide’s efficacy by comparing semaglutide to liraglutide in individuals who previously had lost weight and were at risk of regaining it.18 Although both GLP-1 RAs are highly efficacious, semaglutide users have achieved more significant weight loss from baseline (-15.8%) than liraglutide users (-6.4%) over 68 weeks.18,19
The Semaglutide’s Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) Trial showed a hazard ratio of 0.80 (95% confidence interval [CI], 0.72 to 0.90; P < 0.001), demonstrating that semaglutide reduced the risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (the primary cardiovascular composite endpoint).20 Because of the outcomes from the SELECT Trial, injectable semaglutide (Wegovy) received an expanded indication from the FDA in March 2024 for reducing the risk of stroke and myocardial infarction in adults with a history of cardiovascular disease who are obese or overweight.21
The FDA approved liraglutide (Saxenda) for treating obesity in children 12 years of age and older, providing one of the few options for weight management in adolescents.22 Since this approval for adolescents in 2020, a new clinical trial was published recently to evaluate the safety and efficacy of liraglutide in children ages 6 to < 12 years, which could expand its use to a younger age group.23 The Satiety and Clinical Adiposity — Liraglutide Evidence (SCALE) Kids Trial demonstrated that in children ages 6 to < 12 years with obesity, treatment with liraglutide for 56 weeks, along with lifestyle interventions, resulted in a statistically significantly greater baseline reduction in BMI (-5.8%) compared to placebo with lifestyle interventions (+1.6%) (95% CI, -11.6% to -3.2%; P < 0.001).23
Safety
Adverse reactions: The discontinuation rate for any reason was lower for semaglutide users (13.5%) vs. liraglutide users (27.6%).18 Liraglutide and semaglutide commonly have gastrointestinal (GI) side effects, including nausea, vomiting, and diarrhea caused by medication-induced gastroparesis.11,12 Nausea generally is dose-dependent and does subside over time. Serious but less common effects of liraglutide are acute pancreatitis, gallbladder disease, and renal impairment.11,12
Reports of suicidal ideation associated with semaglutide have begun to raise concerns, causing further investigation.24 However, the FDA reviewed post-marketing surveillance data, and it did not result in evidence that this class of medications can cause suicidal thoughts or actions.25
Additionally, a potential risk for non-arteritic anterior ischemic optic neuropathy (NAION) is associated with semaglutide in a cohort study of 16,827 patients. More research is needed to assess the casualty of NAION.26
GLP-1 and Gastric Inhibitory Polypeptide RA: Tirzepatide
Case Vignette 1, Part 2
The patient mentioned earlier experiences of significant nausea and acid reflux at higher doses of semaglutide. After six weeks of taking the medication, she lost 10 pounds. She is seeking an alternative medication to aid in her weight loss. Her prescriber sent tirzepatide to the pharmacy after discussing the lower levels of nausea typically experienced by patients taking this medication.
Similar to a GLP-1 RA, based on the American Diabetes Association (ADA) 2025 Standards of Care in Diabetes, tirzepatide can be considered the drug of choice for people with T2DM who are attempting to achieve and maintain weight loss goals.6
Background Information
In addition to T2DM, tirzepatide also is FDA-approved for the treatment of obesity. This approval followed the results of the Phase III SURMOUNT-1 and SURMOUNT-2 trials, which demonstrated adults with obesity or excess weight accompanied by weight-related health issues (excluding diabetes) had significant weight loss in addition to that from diet and exercise compared to those on placebo over 72 weeks.27
Mechanism of Action
Tirzepatide is an agonist for GLP-1 and gastric inhibitory polypeptide (GIP) receptors. In addition to the GLP-1 RA mechanism mentioned previously, this medication has GIP receptor activation, promoting insulin release via pancreatic K cells.28 Tirzepatide synergistically promotes glucose-dependent insulin secretion and glucagon suppression by targeting both pathways simultaneously, thereby improving glycemic management in patients with T2DM.29-31
Efficacy/Effectiveness
Clinical trials evaluating the efficacy of tirzepatide have shown a reduction in hemoglobin A1c (HbA1c) and weight loss.31 Tirzepatide is associated with delayed gastric emptying, which can influence the absorption of oral medications, including oral contraceptives.32 As a result of this effect, patients using oral hormonal contraceptives are advised to switch to a non-oral contraceptive method or add a barrier method for additional protection.32 This recommendation applies for four weeks after the initiation of tirzepatide and for four weeks following each dose escalation to ensure effective contraception during potential absorption variability. These precautions aim to prevent reduced contraceptive effectiveness caused by altered drug absorption.
Safety
Tirzepatide generally is well-tolerated in clinical trials, since the safety profile for this novel class is very similar to that of GLP-1 RAs. Many people find less gastrointestinal upset on tirzepatide compared to GLP-1 RAs alone.28 Discontinuation of tirzepatide is most common as the result of gastrointestinal effects.31
The ADA recommends against compounding options for GLP-1 RA and GIP/GLP-1RA classes.32 In January 2025, the ADA issued the following statement:32
Guidance Statements
- Non-FDA-approved compounded incretin products are not recommended for use due to uncertainty about their content and resulting concerns about safety, quality, and effectiveness.
- If an incretin medication is unavailable (e.g., in shortage), switching to a different FDA-approved medication is recommended as clinically appropriate to achieve and maintain individualized glucose-lowering, weight management, and/or cardiovascular and kidney risk reduction goals.
- Upon resolution of incretin product unavailability, reassess the appropriateness of resuming the original FDA-approved incretin medication.
As of the time this paper is being written, the FDA has not reported any national shortages for the GLP-1 RA or GIP/GLP-1 RA classes.
Other Topics Relating to Anti-Obesity Incretin-Based Therapies
Muscle Mass Loss as a Result of Marked Weight Loss Using GLP-1 RAs or GLP-1/GIP RA
The significant weight loss achieved by GLP-1-based medications has raised concerns about the reduction in fat-free mass (FFM), including skeletal muscle mass (SMM), which can account for up to 40% of total weight loss.34 Although the decline in SMM during weight loss has been associated with increased protein breakdown, the effect on physical function appears minimal in most cases.34 Individuals with obesity generally have a higher baseline FFM and SMM than lean individuals, meaning the absolute reduction in SMM is relatively tiny.
Additionally, weight loss improves muscle quality by decreasing intramyocellular and intermuscular triglycerides and enhancing insulin sensitivity.34 However, the heterogeneity in SMM changes among individuals and underscores the importance of further research into the consequences of muscle mass loss brought on by significant weight loss during pharmacotherapy with GLP-1-based agents.
To mitigate muscle mass loss, all patients should be encouraged to participate in regular strength training programs when trying to lose weight, regardless of whether they are taking medications. The American College of Sports Medicine recommends that strength training use each major muscle group two to three days per week on non-consecutive days.35,36 Patients also should be encouraged to work with a personal trainer, exercise physiologist, or physical therapist to learn proper techniques and increase confidence.
Clinical Implications of Discontinuing Anti-Obesity Incretin-Based Agents
Discontinuation of incretin-based, anti-obesity therapies, such as GLP-1 RAs and dual GLP-1/GIP RA, has notable clinical consequences, including significant weight regain and potentially worsening cardiometabolic parameters.36 Semaglutide trials, such as STEP-1 extension and STEP-4, have shown that individuals regain two-thirds of the weight lost during therapy within months of discontinuation, accompanied by worsening glucose levels, blood pressure, and lipid profiles.36-38 Effective discontinuation management involves anticipatory counseling, shared decision-making, and addressing barriers, such as cost and side effects, to mitigate rebound risks and optimize patient outcomes.36
Compounded Options
The ADA Statement on Compounded Incretin Products recommends against using non-FDA-approved compounded options.32 Altthough shortages may exist for incretin-based therapies, compounded options, because they bypass regulatory measures, have potential efficacy and safety concerns. Dosing errors associated with using needle syringes vs. branded prefilled syringes have led to clinically significant adverse side effects. If a particular medication is in short supply locally, the ADA recommends temporarily switching to another FDA-approved medication.
Orlistat
The FDA approved orlistat for obesity management in 1999 because orlistat has been on the market for more than two decades, and long-duration trials have demonstrated its benefits and safety.39-41
Background Information
Orlistat is no longer considered the first-line therapy for obesity management because of its limited tolerability as the result of GI side effects and high attrition rates after the two-year mark.42,43 However, this medication can be considered in patients with a contraindication or intolerance to GLP-1 RAs.
Mechanism of Action
Orlistat alters fat digestion by inhibiting pancreatic lipases to increase fat excretion by about 30%.44
Efficacy
In several randomized trials, a meta-analysis, and a systematic review, orlistat facilitated significant weight loss compared to the control.41,45 Participants taking orlistat for a year lost an average of 3.4 kg (~3.1% of initial weight) more than placebo-treated participants.45
Safety
Adverse effects: Orlistat’s common GI side effects include diarrhea, flatulence, bloating, abdominal pain, dyspepsia, oily spotting, oily/fatty stool, increased defecation, and fecal incontinence.46
Contraindications and warnings: Orlistat is not FDA-approved for children younger than 8 years of age.8 Pregnant women, those with chronic malabsorption, cholestasis, a history of calcium oxalate stones, or those with a known hypersensitivity to orlistat should avoid it.46 Lactating women also should avoid orlistat since it is unknown if it is present in human milk.46
Sympathomimetics
Case Vignette 2, Part 1
Another patient called the clinic a few weeks into taking orlistat with concerns about staining her clothing after bowel movements. She has lost about six pounds, and, overall, did not feel it suppressed her appetite sufficiently. Given this experience, she would like to try something else, such as phentermine. She has a history of hypertension that currently is managed with a low-salt diet and exercise.
Sympathomimetics approved for obesity management are phentermine, benzphetamine, phendimetrazine, and diethylpropion. Phentermine was approved by the FDA in 1959 for short-term weight loss and is a cost-effective weight-loss drug with low rates of abuse.47,48 Although phentermine and diethylpropion are Schedule IV drugs and phendimetrazine is a Schedule III drug, these medications have been shown to have low rates of abuse in clinical practice.47,48
Background Information
These four sympathomimetic medications are approved only for short-term treatment of obesity (up to 12 weeks) because of potential side effects, potential for abuse (because they are classified as scheduled medications), and regulatory surveillance.49-52 Clinicians should prescribe the smallest quantity consistent with quality patient care to minimize the possibility of overdose.49-52
Mechanism of Action
Sympathomimetics increase sympathetic activity to cause early satiety and reduce food intake by stimulating the release of norepinephrine, inhibiting its reuptake into nerve terminals or blocking norepinephrine and serotonin reuptake.53
Efficacy
Two trials for phentermine in Korea showed an average weight loss of 8.1 kg after 12 weeks and an additional 6.7 kg after 24 weeks of use.54,55 The only longer-term controlled trial of phentermine was from 1968. In this study, continuous use of phentermine for more than 36 weeks led to a clinically significant weight reduction of 12.2 kg.56
Safety
Adverse reactions: Sympathomimetics have common side effects related to increased sympathetic activity, including increased heart rate and blood pressure, insomnia, dry mouth, constipation, and nervousness.49,51,52
However, one study reported phentermine usage for obesity was associated with favorable shifts in blood pressure and weight loss and did not result in increased blood pressure or heart rate.47
Contraindications: Patients with cardiovascular disease, hyperthyroidism, glaucoma, an agitated state, or a history of drug abuse should avoid use of sympathomimetics. Sympathomimetics also are contraindicated in patients who are taking monoamine oxidase (MAO) inhibitors (avoid use during or within 14 days following MAO use), are pregnant, or are nursing.49,51,52
Phentermine-Topiramate
Case Vignette 2, Part 2
The second patient taking phentermine was very happy with the weight loss trend of eight pounds in six weeks. She noticed her appetite was blunted only at a higher dose. Unfortunately, as the dose increased, she developed heart palpitations and insomnia. She did not feel her weight reduced on the lowest dose of phentermine alone and wants to try phentermine-topiramate.
The FDA-approved combination of phentermine and topiramate (Qsymia) was introduced in 2012 to treat and manage obesity. Combining two drugs with different mechanisms of action could improve efficacy because multiple pathways influence and regulate food intake.57 Clinically, individuals on this combination generally have fewer side effects from phentermine because of the lower dosage compared to phentermine alone.58
Background Information
Phentermine-topiramate can be considered in individuals without cardiovascular disease (CVD) who do not tolerate orlistat or incretin-based therapies well. Although the combination is more effective than orlistat, it may produce more side effects.59 For individuals stopping this combination, the recommendation is to taper the dose over three to five days.59 Abrupt discontinuation should be avoided because of the risk of seizures.60
Mechanism of Action
As mentioned earlier, phentermine is a sympathomimetic that centrally stimulates the central release of norepinephrine.61 Topiramate’s mechanism of action for weight loss is not entirely understood. However, the effect may be the result of appetite suppression and satiety enhancement based on blocking neuronal voltage-dependent sodium channels, thus enhancing gamma-aminobutyric acid (GABA) activity, antagonizing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA)/kainite glutamate receptors, and weakly inhibiting carbonic anhydrase.62
Efficacy
The CONQUER and EQUIP trials demonstrated that this combination significantly enhanced weight loss in the first year of use but was less effective in maintaining weight loss after the first year.44,45 In both trials, low (7.5 mg/46 mg) and high doses (15 mg/92 mg) of phentermine-topiramate were compared to placebo. In the CONQUER trial, the low- and high-dose groups lost 8.1 kg (P < 0.0001) and 10.2 kg (P < 0.0001) at the one-year mark, respectively.63 In the EQUIP trial, patients had a more significant reduction from baseline body weight on the lower dose (-5.1%) and the higher dose (-10.9%), as compared to the placebo (-1.6%) (P < 0.0001).64
Safety
Adverse reactions: Common side effects include dry mouth, constipation, paresthesia, a dose-related increase in psychiatric and cognitive disturbance, and an increase in heart rate.60,63,64
Contraindications: Avoid the combination of medication in those who are pregnant, have hyperthyroidism, or have glaucoma.60 Discontinue usage within 14 days following the use of MAO inhibitors and use with caution for individuals with a history of kidney stones.60
Naltrexone-Bupropion
Case Vignette 3
A third patient comes to the clinic interested in weight loss. He currently is taking medication-assisted therapy (MAT) for a history of opioid use disorder. He also has a history of seizures. The patient discusses the use of naltrexone-bupropion and learns he is not a candidate for the medication based on its mechanism of action and side effect profile, as discussed in the following section.
The combination of naltrexone-bupropion (Contrave) was approved in September 2014 as an adjunct therapy to diet and exercise in individuals with obesity.65
Background Information
Naltrexone-bupropion is an option for individuals who smoke, have obesity, and are seeking treatment for both; however, this combination is not recommended as a first-line therapy because of the lack of evidence on cardiovascular safety.66-68 The combination has similar efficacy to orlistat but may have more side effects.63 Monitor individuals taking this combination closely for worsening side effects and for the emergence of suicidal thoughts and behaviors.65
Mechanism of Action
Naltrexone and bupropion were found to reduce food intake through complementary mechanisms within the central nervous system. Each drug targets different pathways and, when combined, reduces food intake.69 Bupropion activates the hypothalamic pro-opiomelanocortin (POMC) neurons, which leads to reduced food intake and increased energy expenditure.69 Naltrexone complements this by blocking opioid receptor-mediated auto-inhibition of POMC neurons, thus creating a synergistic effect.69
Efficacy
The combination of naltrexone and bupropion significantly reduced weight in the Contrave Obesity Research (COR) randomized controlled trials.69-72 In the COR-I trial, high (32/360 mg) and low doses (16/360 mg) of naltrexone-bupropion were compared to placebo.71 Participants lost an average of 6.1% (P < 0.001) and 5% (P < 0.001) of body weight in the high- and low-dose groups after 56 weeks, respectively.71 In the COR-II trial, a high combination dose was compared to a placebo.69 Participants lost an average of 6.5% (P < 0.001) of body weight at 28 weeks and 6.4% (P < 0.001) of body weight at 56 weeks.69
Safety
Adverse effects: Common side effects include nausea, headache, constipation, insomnia, vomiting, dizziness, and dry mouth.65 Naltrexone-bupropion should not be used in individuals with uncontrolled hypertension, since this combination can raise blood pressure and heart rate.65 Although few studies have examined the cardiovascular safety of naltrexone-bupropion, a meta-analysis found that the combination was not associated with major cardiovascular adverse events (MACEs) compared with placebo.67,68
Contraindications: Avoid naltrexone-bupropion use in individuals with uncontrolled hypertension, seizure disorder, eating disorder, use of other bupropion-containing products, chronic opioid use, or severe hepatic dysfunction.65 Individuals using chronic opioids may experience opioid withdrawal precipitation because of the naltrexone component. Discontinue the combination drug use during or within 14 days following the use of MAO inhibitors and in pregnancy.65
Clinical Considerations: Clinical Guidelines
The Obesity Medicine Association (OMA)’s Obesity Algorithm 2024 recognizes that obesity is a multifactorial disease that requires a multifaceted, patient-centered, individual approach.8 An individualized plan for weight loss can include one or more of the following: nutrition interventions, physical activity engagement, behavioral modifications, medications, and/or bariatric surgery. The initial step for establishing a patient-centered plan for weight management consists of the patient’s history (for identifying related physical and mental health concerns), a physical examination (including vital signs), and laboratory/diagnostic test results (e.g., measures of glycemia, lipid panel, metabolic panel, and thyroid-stimulating hormone).8
With the initial information, OMA recommends the following key considerations while performing evaluation and assessment:8
- examining preventative standards of medical care;
- recommending nutrition monitoring for energy intake;
- evaluating body systems;
- performing individualized testing if needed (e.g., insulin resistance, hypercortisolism, hyperandrogenemia in women, and hypogonadism in men)
- considering other diagnostic tests (e.g., sleep studies, liver imaging studies, echocardiogram);
- measuring body composition; and
- considering medical conditions that can lead to fat mass accumulation (e.g., untreated hypothyroidism, insulinoma, hypothalamic damage, concurrent medications).
In addition to lifestyle and behavioral interventions, pharmacotherapy for weight management is indicated for certain people with type 2 diabetes and a BMI equal to or above 27 kg/m2.6 The effectiveness of any weight loss agent is defined as losing more than 5% of the initial body weight after three months of use; if this is achieved, further weight loss is possible with the continuation of the therapy.6 Clinical guidelines recommend reevaluating the current treatment strategy with the possibility of intensification if a patient does not achieve treatment goals. Additional approaches to be considered include metabolic surgery, additional pharmacological agents, and structural lifestyle management programs.6
Other Considerations: Obesity-Related Disease States and the Pediatric Population
Obesity is a risk factor for developing many chronic diseases, including T2DM, CVD, and liver disease. This section provides recommendations for T2DM, CVD, and metabolic dysfunction-associated steatotic liver disease (MASLD) patients.
Type 2 Diabetes Mellitus
Obesity can increase the risk of developing T2DM, which is a leading risk factor for CVD. In patients with T2DM and obesity, CVD-associated mortality and morbidity are the highest among all causes.8 By 2025, it is expected that diabetes cases associated with obesity will reach 300 million.73 The ADA stresses combined treatment strategies to induce weight loss and manage glycemic levels in those who are living with obesity and T2DM.6 Selecting a GLP-1 RA or dual receptor RA is considered the drug of choice for individuals with T2DM who need weight reduction.
Cardiovascular Diseases
Among patients with T2DM and obesity, measures for CVD risk reduction are warranted (e.g., making lifestyle modifications related to diet and physical activity, smoking cessation, and managing blood glucose, blood pressure, and lipids). A 10-year observational study in Spain with 899 participants between the ages of 35 and 74 years without evidence of CVD revealed that obesity was not shown to be an independent cardiovascular risk factor.74 However, an increase in weight is associated with fat accumulation (e.g., epicardial and visceral fat), increasing the risk for atherosclerosis and coronary artery calcification.8
Not all agents are appropriate for individuals with uncontrolled cardiovascular conditions. Sympathomimetic agents (such as phentermine and phentermine-topiramate) are contraindicated in patients with uncontrolled hypertension, arrhythmias, and other serious CVD as a result of their stimulatory effects on heart rate and blood pressure. These agents should be used with caution or avoided altogether in such a population.
Heart failure with preserved ejection fraction (HFpEF) may be a direct result of epicardial fat accumulation, since this condition is common among patients with obesity.8 Recent studies have explored the role of incretin-based therapies in patients with HFpEF.75 The STEP-HFpEF trial demonstrated that semeglutide not only promoted weight loss but also improved symptoms, physical function, and inflammatory markers in individuals with obesity and HFpEF. These findings suggest an emerging therapeutic role of GLP-1 RAs in this patient population, pending broader clinical adoption.
Metabolic Dysfunction-Associated Steatotic Liver Disease
Similar to obesity, MASLD may lead to CVD. The majority of patients with MASLD are obese, making screening of MASLD in this population significant. MASLD may progress to metabolic dysfunction-associated steatohepatitis (MASH), defined as the presence of ≥ 5% hepatic fat with inflammation and hepatocyte injury with or without fibrosis.8 When left untreated, MASLD may evolve into hepatocellular carcinoma, indicating a need for a liver transplant. Although some therapeutic agents are in the pipeline and being tested for the treatment of MASH, there are no FDA-approved agents yet; thus, currently, the strategy for managing MASLD is lifestyle modifications with proper nutrition and physical activity, which may lead to weight loss.
Although no anti-obesity pharmacotherapy currently has an FDA-approved indication for MASLD, some agents have shown promise in improving liver-related outcomes in clinical studies. Among these, GLP-1 receptor agonists — specifically semaglutide and liraglutide — have reduced liver fat content and improved histologic markers of steatohepatitis in individuals with MASH and obesity or diabetes.76,77 Tirzepatide also has shown early data indicating reductions in hepatic fat content and liver enzymes.78
Pediatric Obesity
In the United States, childhood and adolescent obesity is an epidemic, with at least 18.5% of children and adolescents being obese.2 Because of the current prevalence and the projected growth in childhood obesity, pediatric obesity is a public health concern, warranting a more robust public health intervention to delay the worsening of the current landscape. Some experts suggest an integrative model where primary and secondary prevention efforts are needed to help reduce current childhood and adolescent obesity.79 Primary prevention efforts focus on educating the entire family on the potential complications resulting from obesity, thus encouraging appropriate lifestyle habits at the child’s young age. Secondary prevention methods emphasize modifying the child’s lifestyle to help them disengage in unhealthy habits, hence aiming to reduce and maintain their weight into adulthood.79
Pharmacotherapeutic Options with FDA Approval for the Pediatric Population
Phentermine-topiramate ER was FDA-approved for weight management in adults with obesity in 2012 and gained approval for use in adolescents in 2022. This approval came after a randomized, double-blind trial in adolescents aged 12 to 17 years with obesity resulted in a significant change in BMI after 56 weeks at -10.4% (95% CI, -13.89% to -6.99%; P < 0.001) compared to placebo.80 Phentermine as a monotherapy also is FDA-approved in adolescents older than 17 years of age.79
Two GLP-1 RAs also have been FDA-approved for use in weight management for adolescents older than 12 years of age: semaglutide (Wegovy) and liraglutide (Saxenda).8 The approval for semaglutide followed the results of the Semaglutide Treatment Effect in People with Obesity (STEP) TEENS Trial.59 Among 180 individuals who completed the trial, the results indicated that by week 68, the mean change in BMI from baseline was -16.1% with semaglutide and 0.6% with placebo (95% CI, -20.3% to -13.2%; P < 0.001).80 Liraglutide is another GLP-1 RA that is FDA-approved for adolescents 12 years of age and older.22 A new trial was published in September 2024, the SCALE Kids Trial, that investigated the efficacy and safety of liraglutide for treating obesity in children aged 6 to 12 years.23 The results demonstrated a significantly more noteworthy baseline reduction in BMI (-5.8%) using treatment with tripeptide along with lifestyle interventions compared to placebo with lifestyle interventions (1.6%) (95% CI, -11.6% to -3.2%; P < 0.001) in the study population.23
Orlistat, which the FDA approved in 2009 for use in children 8 years of age and older, is another option for children and adolescents. A randomized, double-blind study involving 539 adolescents with obesity found that the individuals who took orlistat daily for a year had a BMI reduction of 0.55 kg/m2. At the same time, the placebo group saw a BMI increase of 0.31 kg/m2 (P = 0.001).60
Although these all are valuable options for addressing obesity in pediatric populations, the strategy should be to tailor the pharmacotherapeutic intervention to each individual and integrate behavioral and dietary approaches to achieve lasting health improvements.
Moderate to Severe Obstructive Sleep Apnea
For the first time, a pharmacotherapeutic agent, tirzepatide (Zepbound), has received FDA approval to treat moderate to severe obstructive sleep apnea (OSA) in adults with obesity.81 This groundbreaking approval reflects findings from the SURMOUNT-OSA clinical trials, which demonstrated that tirzepatide significantly reduces apnea-hypopnea index (API) scores in people with OSA and excess weight, offering a non-device-based treatment option that targets an underlying contributor — obesity — while potentially improving cardiometabolic outcomes as well.82
Real-World Applications and Considerations: Discussion
Because of its ever-increasing prevalence in the United States and globally, as well as its potentially profound effect on morbidity and mortality, obesity continues to be one of the most difficult challenges in the current healthcare system. The landscape of pharmacological interventions has evolved tremendously in recent years. The currently available pharmacotherapeutic options, with the recent FDA-approved agents semaglutide and tirzepatide, offer those struggling with obesity various tools to potentially overcome such challenges in accomplishing significant weight loss and maintaining their weight at the reduced level. This review article highlights the efficacy and safety of each FDA-approved medication or medication combination for treating obesity and special considerations for use in various populations.
Evolving Treatment Paradigms in Obesity
The obesity pharmacotherapy space has shifted significantly since the approval of incretin-based therapies and because of their continuous development. These medications have shown tremendous outcomes in weight loss, now being considered the drug of choice for this purpose, with the potential weight loss outcomes approaching those of bariatric surgery in some cases.83 The newer trial series in this space — STEP and SURMOUNT — have shared robust evidence for the efficacy of injectable semaglutide and tirzepatide, respectively. In addition to weight loss, injectable semaglutide also has been shown (through the SELECT trial) to be effective for preventing atherosclerotic cardiovascular disease events in individuals with obesity or overweight, thus leading to an expansion on Wegovy’s indications in March 2024.20,81
The shift toward using the newer incretin-based agents reflects a growing understanding of obesity’s pathophysiology. By targeting various pathways involved in appetite regulation and energy metabolism, these agents offer a more comprehensive approach to weight reduction than the previously employed single-target therapies.
Personalized Approach to Obesity Pharmacotherapy: Incretin-Based Therapies
A key takeaway from the current literature is individualizing treatment strategies based on person-specific characteristics and preferences. Medications such as liraglutide and injectable semaglutide have led to substantial weight loss and additional cardiometabolic benefits, specifically for those with T2DM and a history of CVD, many of whom also might be managing their weight. Clinical trials, such as STEP and SELECT, have highlighted the efficacy of injectable semaglutide in reducing cardiovascular events in people with obesity while promoting weight reduction. The weekly dosing of semaglutide improves consistent medication-taking habits, making this agent a preferred option for many individuals over daily injections of liraglutide.
The emergence of a dual-receptor, incretin-based therapy — tirzepatide — has pushed overall obesity pharmacotherapy to a different level, offering another weekly injectable option. The SURMOUNT trials have demonstrated promising weight loss results, suggesting that tirzepatide can be a front-line agent, particularly in individuals with T2DM.6 Its efficacy in reducing and maintaining HbA1c, combined with its milder GI side effect profile compared to semaglutide, highlights its potential as a long-term treatment option.
Barriers to Access and Long-Term Considerations
Many obesity pharmacotherapeutic agents, particularly the newer agents, are expensive and may not be covered (or only partially covered) by insurance, limiting their access to those who need them. For this reason, barriers to access continue to impair widespread use, leading to health inequity. Because of the chronic nature of obesity, many individuals might need these medications for the long term. Still, data on the long-term efficacy and safety of an extended period of such medications are limited.
The weight potentially regained after discontinuing the medication emphasizes the need for strategies to implement comprehensive lifestyle interventions, such as modifying eating habits and daily physical activity, to maintain weight loss over time.
Future Directions
The future of obesity pharmacotherapy stems from the continued development of more effective options with fewer side effects and broader accessibility, as well as from making the existing agents more accessible to those who need them to advance health equity. Novel agents, such as tirzepatide, signify a shift toward therapeutic agents that not only achieve weight reduction but also address comorbid conditions such as T2DM and CVD. Integrating personalized medicine, where genetic and phenotypic data inform treatment decisions, may further enhance treatment outcomes as technology advances.
Conclusion
Obesity management must be multifaceted, combining pharmacological interventions with consistent lifestyle modifications and maintenance. Although the medications reviewed in this article have provided opportunities to improve weight loss and mitigate the associated health risks, carefully considering person-specific characteristics and the agents’ potential side effects is critical to optimizing treatment outcomes.
Joy Moverley, DHSc, MPH, PA-C, is Professor and Program Director, Touro University California Joint MSPAS/MPH Program, Vallejo, CA.
Bhavya Chhabra, OMS-IV, is a student at Touro University California College of Osteopathic Medicine, Vallejo, CA.
Kasra Soltani Nia, OMS-IV, is a student at Touro University California College of Osteopathic Medicine, Vallejo, CA.
Kirsten Alliston, MPH(c), PA-S3, is with the Touro University California Joint MSPAS/MPH Program, Vallejo, CA.
Clipper F. Young, PharmD, MPH, BC-ADM, CDCES, BCGP, APh, FADCES, is Associate Professor and Clinical Pharmacist and Director of Clinical Research, Touro University California College of Osteopathic Medicine, Vallejo, CA.
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Obesity poses a significant public health and economic burden, contributing to numerous chronic conditions. This review provides primary care providers with a concise overview of U.S. Food and Drug Administration-approved pharmacotherapies for obesity management, including incretin-based treatments that rival bariatric surgery in efficacy. It emphasizes the importance of aligning pharmacologic options with individual patient profiles and comorbidities, reinforcing that lifestyle modification remains a critical component of successful, sustained weight loss.
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